Main outcome measures

Main results

At 1 year, and after assessment with endoscopy, 89% of patients taking daily omeprazole
were in remission compared with 32% of patients taking weekend omeprazole (95% CI
for 57% difference 42% to 71%) and 25% of patients taking ranitidine (CI for 64% difference
50% to 78%). Symptoms of esophagitis showed a similar pattern. The groups did not
differ for gastrin concentrations, pathologic findings, or adverse effects.

Conclusions

Daily omeprazole (20 mg/d) was safe and effective for preventing relapse and symptoms
of esophagitis. Omeprazole taken 3 times/wk plus ranitidine was not effective.

Commentary

Marks and colleagues report a complex study that showed that healing of erosive esophagitis
in patients with associated peptic stricture results in significant dysphagia relief
and decreased need for dilation. These improvements were observed independent of the
rate of stricture resolution. Additionally, the authors address issues of clinical
efficacy and cost-effectiveness.

Marks and colleagues compared omeprazole with H2RAs, knowing beforehand that a difference in healing rates would exist. They created
an elegant stratification scheme and used the anticipated difference in healing rates
to study the relative contributions of erosive esophagitis and stricture to symptoms
of dysphagia and dilatation requirements. The research design works well for probing
the pathophysiologic mechanisms underlying dysphagia; however, the type of blinding
used could affect the appropriateness of this design for a clinical efficacy study.

The cost-effectiveness analysis was carried out within the context of the protocol
and, therefore, may not accurately reflect costs in an open clinical situation. For
instance, it is unlikely that patients in the asymptomatic peptic stricture group
would be given endoscopy after 3 months of successful acid-suppression therapy. Therefore,
the cost advantage of omeprazole therapy may be understated. Alternatively, impending
patent expirations and price competition among the H2RAs is decreasing their costs. This is particularly true of cimetidine, which was
not included among the H2RAs studied. Therefore, the cost disadvantage for H2RAs may be overstated.

The observation that healing erosive esophagitis independently improves dysphagia
and dilatation requirements in patients with peptic stricture is extremely important
and has immediate clinical applicability. The other goals of the study are more open
to varied interpretations and may obscure the important primary finding.

James and Parry-Billings present data confirming that in young and old patients, antisecretory
therapy with omeprazole is superior to therapy with H2RAs for healing esophagitis and relieving reflux symptoms. Unfortunately, the study
methods used may not detect the subtle difference in age-associated therapy responses
sought by the authors.

The study is a retrospective analysis of combined data obtained from 2 multicenter
trials done in the United Kingdom and Ireland. True differences may exist between
the populations. For example, longevity may differ between the United Kingdom and
Ireland. Other differences can easily be postulated. Although the authors state that
the 2 protocols used to accrue patients were similar, they do not provide protocol-specific
information about demographic characteristics of the patients actually accrued (other
than percentage of persons who smoked and percentage of persons who consumed alcohol)
or how they were distributed among groups analyzed after combining the 2 populations.

It is unclear how the authors selected the age of 65 years or greater to define "old."
In general, an appropriate definition of "old" is lacking in the literature on aging.
Application of cluster analysis to the data presented might show age groupings at
which significant differences in therapeutic response occur. These groupings could
be used to define "young" and "old." An appropriately stratified prospective study
might then confirm differences postulated on the basis of cluster analysis.

Should we believe that no age differences exist? Not on the basis of data presented
by James and Parry-Billings. If differences exist, are they likely to alter the apparent
superiority of omeprazole to H2RAs in all age groups? No.

The study by Dent and colleagues confirms observations made by most clinicians and
some investigators (1) shortly after omeprazole became available. Conventional-dose omeprazole is far superior
to H2RAs for maintenance therapy of erosive esophagitis. Attempts to cycle patients off
omeprazole, ostensibly to avoid argyrophil cell hyperplasia and gastric carcinoid
tumors, were notoriously unsuccessful with regard to symptoms and clinical findings
(2). More often than not, clinicians were faced with miserable patients begging to be
put back on omeprazole and complaining about the costs of double-dose H2RA therapy.

A most useful aspect of this investigation is the valuable histologic data generated
that confirm previous work suggesting that long-term omeprazole therapy does not induce
neoplastic change in the argyrophilic cell population of the human gastric oxyntic
mucosa. Dent and colleagues' statistical treatment of therapy related to argyrophilic
cell population and serum gastrin changes is rather obscure but is necessitated by
the occurrence of outliers that significantly skew the sample means. Examination of
box plots in Figures 5 and 6 of the article shows the outlier phenomenon to be pronounced
for serum gastrin levels and minimal for argyrophilic cell population estimates. Indeed,
the authors revert to discussing the sample means in their treatment of argyrophilic
cell population estimates.

An analysis of the correlation between serum gastrin levels and argyrophilic cell
population estimates would have been most enlightening. Are gastrin level outliers
associated with outliers for larger values for argyrophilic cell populations? Does
a subpopulation of patients receiving long-term omeprazole therapy exist that might
warrant further study? Dent and colleagues stopped just short of providing some much-needed
insight into this phenomenon. Perhaps we will hear from them later on this topic.
They appear to have the data.

This triad of articles substantially improves our knowledge of omeprazole efficacy
and safety in the management of gastroesophageal reflux disease and gives scientific
legitimacy to many common management practices. Marks and colleagues show that omeprazole
is an effective tool in the treatment of dysphagia arising from strictures associated
with erosive esophagitis. James and Parry-Billings attempt to assure us that omeprazole
is superior to H2RAs in both young and old but leave us wondering what it means to be "old." Dent and
colleagues report the first randomized, double-blind, controlled trial comparing the
efficacy of omeprazole with that of an H2RA for the prevention of relapse in reflux esophagitis. They have succeeded in scientifically
confirming what our patients have long been telling us, but, more importantly, their
data suggest that maintenance therapy with omeprazole is safe and does not induce
neoplastic change in the argyrophilic cell population of the human gastric oxyntic
mucosa.